Anti-MHC Class I Antibody Activation of Proliferation and Survival Signaling in Murine Cardiac Allografts

Jindra, Peter T.; Hsueh, Aileen; Hong, Longshen; Gjertson, David W.; Shen, Xiu Da; Gao, Feng; Dang, Julie; Mischel, Paul S.; Baldwin, William M.; Fishbein, Michael C.; Kupiec‐Weglinski, Jerzy W.; Reed, Elaine F.

doi:10.4049/jimmunol.180.4.2214

Cited by 94 publications

(109 citation statements)

References 59 publications

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“…[11][12][13][14] Here, patients with DSA anti-HLA antibodies against class II molecules had elevated levels of EndMT markers, and the PTC expressed fascin de novo in an experimental model of ABMR. These findings confirm that these DSAs are harmful for endothelial cells that survive immunologic injury.…”

Section: Discussionmentioning

confidence: 77%

“…In vitro and in vivo experiments, [11][12][13][14] as well as human data from kidney recipients, 4 concur to show that the binding of DSA to endothelial cells profoundly affects the endothelial transcriptome. Molecules involved in inflammation, coagulation, cell motility, and endothelial repair are synthesized, with phenotypic changes reminiscent of an endothelial-tomesenchymal transition (EndMT).…”

mentioning

confidence: 75%

“…Molecules involved in inflammation, coagulation, cell motility, and endothelial repair are synthesized, with phenotypic changes reminiscent of an endothelial-tomesenchymal transition (EndMT). 3,13,14 Just like its epithelial counterpart, EndMT occurs under different stimuli, [15][16][17] which contribute to fibrogenesis in animal models of renal and cardiac fibrosis. 18,19 The aim of our work was to test the hypothesis that expression of EndMT markers could serve as evidence of current endothelial reaction following DSA binding and/or complement activation and thus help to consolidate the diagnosis of ABMR in renal grafts.…”

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confidence: 99%

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Markers of Endothelial-to-Mesenchymal Transition

Xu‐Dubois

Peltier

Brochériou

et al. 2016

Journal of the American Society of Nephrology

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Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. Treatment efficacy depends on accurate diagnosis at an early stage. However, sensitive and reliable markers of antibody-endothelium interaction during ABMR are not available for routine use. Using immunohistochemistry, we retrospectively studied the diagnostic value of three markers of endothelial-to-mesenchymal transition (EndMT), fascin1, vimentin, and heat shock protein 47, for ABMR in 53 renal transplant biopsy specimens, including 20 ABMR specimens, 24 cell-mediated rejection specimens, and nine normal grafts. We validated our results in an independent set of 74 unselected biopsy specimens. Endothelial cells of the peritubular capillaries in grafts with ABMR expressed fascin1, vimentin, and heat shock protein 47 strongly, whereas those from normal renal grafts did not. The level of EndMT marker expression was significantly associated with current ABMR criteria, including capillaritis, glomerulitis, peritubular capillary C4d deposition, and donor-specific antibodies. These markers allowed us to identify C4d-negative ABMR and to predict late occurrence of disease. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR and predicted late (up to 4 years after biopsy) renal graft dysfunction and proteinuria. In the independent set of 74 renal graft biopsy specimens, the EndMT markers for the diagnosis of ABMR had a sensitivity of 100% and a specificity of 85%. Fascin1 expression in peritubular capillaries was also induced in a rat model of ABMR. In conclusion, EndMT markers are a sensitive and reliable diagnostic tool for detecting endothelial activation during ABMR and predicting late loss of allograft function.

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Section: Discussionmentioning

confidence: 77%

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confidence: 75%

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confidence: 99%

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Markers of Endothelial-to-Mesenchymal Transition

Xu‐Dubois

Peltier

Brochériou

et al. 2016

Journal of the American Society of Nephrology

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“…Furthermore, passive transfer of anti-donor MHC class I antibodies to experimental heart transplant recipients lacking T and B lymphocytes induces TV [31]. We reported activation of the mTOR pathway in capillary and intramyocardial artery and vein endothelium of cardiac allografts from T and B cell deficient RAG1.KO hosts that were passively transfused with antidonor MHC class I antibody [32]. The mTOR pathway has been shown to play a critical role in the process of vascular intimal proliferation.…”

Section: Discussionmentioning

confidence: 97%

MHC class I and integrin ligation induce ERK activation via an mTORC2-dependent pathway

Jindra

Jin

Jácamo

et al. 2008

Biochemical and Biophysical Research Communications

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The aim of this study was to characterize the interaction between mTOR and ERK in primary endothelial cells (EC) following MHC class I and integrin ligation. Ligation of MHC class I molecules or integrins on the surface of EC leads to phosphorylation of ERK at Thr202/Tyr204. We utilized small interfering RNA (siRNA) blockade of mTOR and proteins involved in mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) to define a relationship between mTOR and ERK following MHC class I signaling. We found mTORC2 was responsible for MHC class I and integrin induced phosphorylation of ERK at Thr202/Tyr204. We corroborated these results demonstrating that long-term exposure to rapamycin also inhibited ERK pathway activation in response to MHC class I signaling. Our results demonstrate, for the first time, that engagement of either MHC class I or integrin on the surface of EC leads to ERK activation through an mTORC2-dependent pathway. KeywordsMHC; HLA class I; ERK; mTORC2; siRNA; Endothelial cells; Signal transduction mTOR plays an essential role in integrin and MHC class I-induced cell proliferation and survival through formation of two distinct multi-protein molecular complexes, mTORC1 and mTORC2 [1][2][3][4]. mTORC1 consists of mTOR in association with regulatory associated protein of mTOR (Raptor) and GβL [5]. mTORC1 phosphorylates p70 S6 Kinase and eukaryotic initiation factor 4E binding protein 1 which activate translational machinery to increase cell proliferation [6,7]. mTORC2 is composed of mTOR binding to rapamycin insensitive companion of mTOR (Rictor), GβL, stress-activated protein kinase-interacting protein 1 (Sin1) and the newly discovered associations with PRoline-Rich protein 5 (PRR5) or the synonymous protein observed with Rictor 1 (Protor-1), and P-REX1 [8][9][10][11][12]. mTORC2 activates Akt at Ser473, Rac GTPase, cell migration and effects reorganization of the actin cytoskeleton [11][12][13][14]. Recent work utilizing mouse knockout models emphasizes the importance of mTOR for growth and proliferation in development [15,16]. Homozygous mTOR (−/−) mice have * Corresponding author: Fax: + 1 310 206 3216; Email address: ereed@mednet.ucla.edu (E. F. Reed). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [17,18]. These data show both mTOR complexes are involved in signal transduction leading to cell proliferation, however, the mechanism(s) by which mTORC2 participates in mitogenic signaling remains less well defined. NIH Public AccessERK1/2 are members of a family of serine/threonine kinases activated by a variety of growth factors, cell surface receptors, int...

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“…Therefore, the interpretation of these findings will require further validation in a suitable in vivo transplant model. We recently developed a mouse vascularized heterotopic cardiac allograft model in which B6.RAG1 knockout hosts receive a fully MHC-incompatible BALB/c heart transplant and are passively transfused with anti-donor MHC class I Abs (48). Cardiac allografts of mice treated with anti-MHC class I Abs showed characteristic features of Ab-mediated rejection and prominent phosphorylation of Akt at Ser 473 and S6K at Thr 421 /Ser 424 .…”

Section: Discussionmentioning

confidence: 99%

HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway

Jindra¹,

Jin²,

Rozengurt

et al. 2008

The Journal of Immunology

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144

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Anti-HLA Abs have been shown to contribute to the process of transplant vasculopathy by binding to HLA class I molecules expressed by the endothelial and smooth muscle cells of the graft and transducing intracellular signals that elicit cell proliferation. The aim of this study was to determine the role of mammalian target of rapamycin (mTOR) in HLA class I-induced endothelial cell proliferation and to explore in depth the relationship between mTOR complexes and their downstream targets following ligation of HLA class I molecules by anti-HLA Abs. We used small interfering RNA technology to abrogate mTOR, rapamycin-insensitive companion of mTOR (rictor), or regulatory associated protein of mTOR (raptor) to study the function of these gene products to activate proteins involved in MHC class I-induced cell proliferation and survival. Knockdown of mTOR inhibited class I-mediated phosphorylation of proteins downstream of mTOR complex 1 and mTOR complex 2. Furthermore, knockdown of mTOR, rictor, or raptor blocked HLA class I-induced endothelial cell proliferation. Long-term pretreatment with the mTOR inhibitor rapamycin significantly blocked both mTOR-raptor and mTOR-rictor complex formation. Interestingly, rapamycin also blocked class I-induced Akt phosphorylation at Ser473 and Bcl-2 expression. These results support the role of anti-HLA Abs in the process of transplant vasculopathy and suggest that exposure of the graft endothelium to anti-HLA Abs may promote proliferation through the mTOR pathway.

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Anti-MHC Class I Antibody Activation of Proliferation and Survival Signaling in Murine Cardiac Allografts

Cited by 94 publications

References 59 publications

Markers of Endothelial-to-Mesenchymal Transition

Markers of Endothelial-to-Mesenchymal Transition

MHC class I and integrin ligation induce ERK activation via an mTORC2-dependent pathway

HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway

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